Synthetic lactone formulations and method of use

ABSTRACT

Natural and synthetic compounds having a lactone structure methods for alleviation of pain, especially pain associated with disorders such as melanoma, leukemia, breast cancer, lung cancer, ovarian cancer, colon cancer, esophagus cancer, liver cancer, and lymphatic cancer. Initial studies have shown that patients can be taken off of morphine when the preferred alpha-methylene-gamma-butyrolactone is administered in a dosage of between 60 and 120 mg/day intramuscularly.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of pending prior application U.S.Ser. No. 11/108,198, filed Apr. 18, 2005, entitled “SYNTHETIC LACTONEFORMULATIONS AND METHOD OF USE”, by Frederico M. Gomez and C. FredericoGomez Garcia-Godoy, which claims priority to under 35 U.S.C. §119 toU.S. Provisional Application No. 60/565,114, filed Apr. 23, 2004, all ofwhich are herein incorporated in their entirety by reference.

FIELD OF THE INVENTION

The present inventions are generally in the fields of pharmaceuticallyactive lactones, their pharmaceutical formulations, and methods of usefor treating pain.

BACKGROUND OF THE INVENTION

Despite the development of many different compounds which are useful inthe treatment of pain, there remains a need for the development of newcompounds which may be effective at lower dosages, are lesshabit-forming and have fewer side effects.

It is therefore an object of this invention to provide a new class ofcompounds that effectively treat pain.

It is another object of this invention to provide a new class ofcompounds that are effective at treating pain and are lesshabit-forming.

SUMMARY OF THE INVENTION

Dosage formulations containing an effective amount of a lactone compoundof Formulae Ia, Ib, and Ic in a pharmaceutically acceptable carrier, toalleviate pain, have been developed. The lactone compound can beadministered as the free base or a pharmaceutically acceptable salt orhydrate thereof. Studies have demonstrated that these compounds areuseful as anti-bacterial, anti-fungal and anti-inflammatory agents, andfor treating proliferation disorders such as melanoma, leukemia, breastcancer, lung cancer, ovarian cancer, colon cancer, esophagus cancer,liver cancer, and lymphatic cancer, as well as for treating painassociated with these disorders. Patients report that they are able tobe removed from morphine when treated with the compounds disclosedherein, especially alpha-methylene-gamma-butyrolactone.

DETAILED DESCRIPTION OF THE INVENTION

I. Lactone Compositions

A. Lactones.

Lactones and their respective derivatives with a hydroxyl in the gammaposition are disclosed. The lactones and the derivatives thereof can besynthesized or isolated from natural sources. In one embodiment, thelactones and the derivatives can be isolated by means of chromatographicmethods, from a plant whose taxonomic scientific name is Securidacavirgata, which belongs to the botanical family Polygalaceae. As usedherein, the term “lactones” encompasses any organic compounds having afive-member ring lactone structure in which the oxygen atom of the C═Ogroup can be replaced by a sulfur atom or a nitrogen grouping. The term“derivatives” as used herein refers to any compounds that are made fromthe lactones by reacting the lactones with one or more chemicalreagents. The term also refers to any products obtainable by ringopening of the lactones with an organic or inorganic nucleophilic agentsto form, for example, an acid, ester, amide, or any other productsthereof.

In one embodiment, the lactone has the following chemical structure:

wherein

R₁-R₆ taken independently are a hydrogen atom, a halogen atom, ahydroxyl group, or any other organic groupings containing any number ofcarbon atoms, preferably 1-8 carbon atoms, and optionally include aheteroatom such as oxygen, sulfur, or nitrogen grouping in linear,branched, or cyclic structural formats, representative R₁-R₆ groupingsbeing H, alkyl, substituted alkyl, allyl, substituted allyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, phenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl,alkoxy, substituted alkoxy, alloxy, phenoxy, substituted phenoxy, aroxy,substituted aroxy, alkylthio, substituted alkylthio, phenylthio,substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano,substituted isocyano, carbonyl, substituted carbonyl, carboxyl,substituted carboxyl, amino, substituted amino, amido, substitutedamido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl,substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl,substituted polyaryl, C₁-C₂₀ cyclic, substituted C₁-C₂₀ cyclic,heterocyclic, substituted heterocyclic, aminoacid, peptide, orpolypeptide group;

Z is a heteroatom such as oxygen, sulfur, or nitrogen grouping inlinear, branched, or cyclic structural formats; and

X is a heteroatom such as oxygen, sulfur, or nitrogen grouping inlinear, branched, or cyclic structural formats.

In another embodiment, the lactone has the following chemical structure:

wherein

R₁-R₄ taken independently may be a hydrogen atom, a halogen atom, ahydroxyl group, or any other organic groupings containing any number ofcarbon atoms, preferably 1-8 carbon atoms, and optionally include aheteroatom such as oxygen, sulfur, or nitrogen grouping in linear,branched, or cyclic structural formats, representative R₁-R₄ groupingsbeing H, alkyl, substituted alkyl, allyl, substituted allyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substitutedphenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,halo, hydroxyl, alkoxy, substituted alkoxy, alloxy, phenoxy, substitutedphenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio,phenylthio, substituted phenylthio, arylthio, substituted arylthio,cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl,carboxyl, substituted carboxyl, amino; substituted amino, amido,substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid,phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl,polyaryl, substituted polyaryl, C1-C20 cyclic, substituted C₁-C₂₀cyclic, heterocyclic, substituted heterocyclic, aminoacid, peptide, orpolypeptide group;

X is a heteroatom such as oxygen, sulfur, or nitrogen grouping inlinear, branched, or cyclic structural formats; and

Z is a heteroatom such as oxygen, sulfur, or nitrogen grouping inlinear, branched, or cyclic structural formats.

In still another embodiment, the lactones having an alpha-methylenegroup can have the structure as show below:

wherein

R₁-R₄ taken independently may be a hydrogen atom, a halogen atom, ahydroxyl group, or any other organic groupings containing any number ofcarbon atoms, preferably 1-8 carbon atoms, and optionally include aheteroatom such as oxygen, sulfur, or nitrogen grouping in linear,branched, or cyclic structural formats, representative R₁-R₄ groupingsbeing alkyl, allyl, substituted alkyl, alkenyl, allyl, substitutedallyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl,substituted phenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, alloxy, phenoxy,substituted phenoxy, aroxy, substituted aroxy, alkylthio, substitutedalkylthio, phenylthio, substituted phenylthio, arylthio, substitutedarylthio, cyano, isocyano, substituted isocyano, carbonyl, substitutedcarbonyl, carboxyl, substituted carboxyl, amino, substituted amino,amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid,phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl,polyaryl, substituted polyaryl, C1-C20 cyclic, substituted C₁-C₂₀cyclic, heterocyclic, substituted heterocyclic, aminoacid, peptide, orpolypeptide group;

Z is a heteroatom such as oxygen, sulfur, or nitrogen grouping inlinear, branched, or cyclic structural formats; and

X is a heteroatom such as oxygen, sulfur, or nitrogen grouping inlinear, branched, or cyclic structural formats.

In a preferred embodiment, the lactone is α-methylene-γ-butyrolactone,also known as Securolide, which has the structure shown below:

The pharmaceutically acceptable acid addition salts of compounds of theformula Ia, Ib, or Ic, may be prepared in a conventional manner bytreating a solution or suspension of the free base of the formula 1 withabout one chemical equivalent of a pharmaceutically acceptable acid.Conventional concentration and recrystallization techniques can beemployed to isolate the salt.

The pharmaceutically acceptable base addition salts of compounds offormula 1 containing an acid group may be prepared in a conventionalmanner from the acid, e.g. by reaction with about one chemicalequivalent of a base.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, naphthalenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, and isethionic.

The pharmaceutically acceptable salts of the compounds can besynthesized from the parent compound, which contains a basic or acidicmoiety, by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins,Baltimore, Md., 2000, p. 704.

B. Excipients

The lactone and functional derivatives can be formulated using standardtechniques for enteral, parenteral, topical administration (see, forexample, Encyclopedia of Controlled Drug Delivery, Edith Mathiowitz,Ed., John Wiley & Sons, Inc., New York, 1999). Effective dosages can bedetermined based on the in vitro assays known to those skilled in theart, such as the assays described in the examples.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problems or complicationscommensurate with a reasonable benefit/risk ratio.

Suitable pharmaceutically acceptable vehicles for parenteral deliveryinclude sterile saline, phosphate buffered saline, apyrogenic sterilevehicle, and standard microparticulate formulations for injection,including polymeric microspheres, microcapsules, liposomes, andemulsions. These can include degradable polymers such as polylactic acidand polyglycolic acid, and copolymers thereof, polyanhydrides,polyorthoesters, and polyhydroxyalkanoates.

Suitable pharmaceutically acceptable carriers include talc, gum Arabic,lactose, starch, magnesium stearate, cocoa butter, aqueous ornon-aqueous vehicles, fatty substances of animal or vegetable origin,paraffin derivatives, glycols, various wetting, dispersing oremulsifying agents and preservatives.

For injection, the lactones will typically be formulated as solutions orsuspensions in a liquid carrier.

For topical delivery, the lactone may be formulated in an ointment,creams, lotion, gel, spray, or controlled or sustained releaseformulation (such as a transdermal patch).

For enteral delivery, the lactone may be formulated in a tablet,capsule, granule, suppository, suspension or solution, dissolved orencapsulated in an excipient such as a sugar like lactose, inertcompound such as magnesium stearate, paraffin derivatives, glycols orgum arabic. The formulations may further include dyes, flavorings,preservatives, dispersing or emulsifying agents, or materials modifyingrelease or stability properties of the formulations.

Formulations are prepared using a pharmaceutically acceptable “carrier”composed of materials that are considered safe and effective and may beadministered to an individual without causing undesirable biologicalside effects or unwanted interactions. The “carrier” is all componentspresent in the pharmaceutical formulation other than the activeingredient or ingredients. The term “carrier” includes but is notlimited to diluents, binders, lubricants, desintegrators, fillers, andcoating compositions.

“Carrier” also includes all components of the coating composition whichmay include plasticizers, pigments, colorants, stabilizing agents, andglidants. The delayed release dosage formulations may be prepared asdescribed in references such as “Pharmaceutical dosage form tablets”,eds. Liberman et. al. (New York, Marcel Dekker, Inc., 1989),“Remington—The science and practice of pharmacy”, 20th ed., LippincottWilliams & Wilkins, Baltimore, Md., 2000, and “Pharmaceutical dosageforms and drug delivery systems”, 6^(th) Edition, Ansel et. al., (Media,Pa.: Williams and Wilkins, 1995) which provides information on carriers,materials, equipment and process for preparing tablets and capsules anddelayed release dosage forms of tablets, capsules, and granules.

Examples of suitable coating materials include, but are not limited to,cellulose polymers such as cellulose acetate phthalate, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate and hydroxypropyl methylcellulose acetate succinate; polyvinylacetate phthalate, acrylic acid polymers and copolymers, and methacrylicresins that are commercially available under the trade name Eudragit®(Roth Pharma, Westerstadt, Germany), Zein, shellac, and polysaccharides.

Additionally, the coating material may contain conventional carrierssuch as plasticizers, pigments, colorants, glidants, stabilizationagents, pore formers and surfactants.

Optional pharmaceutically acceptable excipients present in thedrug-containing tablets, beads, granules or particles include, but arenot limited to, diluents, binders, lubricants, disintegrants, colorants,stabilizers, and surfactants.

Diluents, also termed “fillers,” are typically necessary to increase thebulk of a solid dosage form so that a practical size is provided forcompression of tablets or formation of beads and granules. Suitablediluents include, but are not limited to, dicalcium phosphate dihydrate,calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose,microcrystalline cellulose, kaolin, sodium chloride, dry starch,hydrolyzed starches, pregelatinized starch, silicone dioxide, titaniumoxide, magnesium aluminum silicate and powder sugar.

Binders are used to impart cohesive qualities to a solid dosageformulation, and thus ensure that a tablet or bead or granule remainsintact after the formation of the dosage forms. Suitable bindermaterials include, but are not limited to, starch, pregelatinizedstarch, gelatin, sugars (including sucrose, glucose, dextrose, lactoseand sorbitol), polyethylene glycol, waxes, natural and synthetic gumssuch as acacia, tragacanth, sodium alginate, cellulose, includinghydrorxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose,and veegum, and synthetic polymers such as acrylic acid and methacrylicacid copolymers, methacrylic acid copolymers, methyl methacrylatecopolymers, aminoalkyl methacrylate copolymers, polyacrylicacid/polymethacrylic acid and polyvinylpyrrolidone.

Lubricants are used to facilitate tablet manufacture. Examples ofsuitable lubricants include, but are not limited to, magnesium stearate,calcium stearate, stearic acid, glycerol behenate, polyethylene glycol,talc, and mineral oil.

Disintegrants are used to facilitate dosage form disintegration or“breakup” after administration, and generally include, but are notlimited to, starch, sodium starch glycolate, sodium carboxymethylstarch, sodium carboxymethylcellulose, hydroxypropyl cellulose,pregelatinized starch, clays, cellulose, alginine, gums or cross linkedpolymers, such as cross-linked PVP (Polyplasdone XL from GAF ChemicalCorp).

Stabilizers are used to inhibit or retard drug decomposition reactionswhich include, by way of example, oxidative reactions.

Surfactants may be anionic, cationic, amphoteric or nonionic surfaceactive agents. Suitable anionic surfactants include, but are not limitedto, those containing carboxylate, sulfonate and sulfate ions. Examplesof anionic surfactants include sodium, potassium, and ammonium salts oflong chain alkyl sulfonates and alkyl aryl sulfonates such as sodiumdodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodiumdodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodiumbis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodiumlauryl sulfate. Cationic surfactants include, but are not limited to,quaternary ammonium compounds such as benzalkonium chloride,benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzylammonium chloride, polyoxyethylene and coconut amine. Examples ofnonionic surfactants include ethylene glycol monostearate, propyleneglycol myristate, glyceryl monostearate, glyceryl stearate,polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates,polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylenetridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401,stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallowamide. Examples of amphoteric surfactants include sodiumN-dodecyl-.beta.-alanine, sodium N-lauryl-.beta.-iminodipropionate,myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.

If desired, the tablets, beads granules or particles may also containminor amount of nontoxic auxiliary substances such as wetting oremulsifying agents, dyes, pH buffering agents, and preservatives.

The amount of active agent released in each dose will be atherapeutically effective amount.

The active compound may be used in combination with a secondpharmaceutically acceptable antimicrobial agent such as nitroimidazoleantibiotics, e.g. timidazole and metronidazole; tetracyclines, e.g.tetracycline, doxycycline and minocycline; penicillins, e.g. amoxicillinand meziocillin; cephalosporins, e.g. cefaclor, cefadroxil, cephadrine,cefuroxime, cefuroxime axetil, cephalexin, cefpodoxime proxetil,ceftazidime and cefatriaxone; carbapenems, e.g. imipenem and meropenem;aminoglycosides, e.g. paromomycin; macrolide antibiotics, e.g.erythromycin, clarithromycin and azithromycin; lincosamide antibiotics,e.g. clindamycin; rifamycins, e.g. rifampicin; and nitrofurantoin.

Combinations of the compounds with a pharmaceutical acid-lowering agentmay used in the treatment of acid-related disorders, such as acid pumpinhibitors, e.g., omeprazole and lansoprazole, or H₂ antagonists, e.g.,ranitidine, cimetidine, and famotidine:

II. Synthesis of Lactones

The synthesis of the lactones of formulae Ia, Ib, and Ic involves: a)forming an intermediate or precursor having the lactone structure, andb) reacting the intermediate with one or more appropriate chemicalagents to form the lactones of formulae Ia, Ib, and Ic.

In one embodiment, the method involves: a) providing a precursor havingthe following structure:

and b) reacting the precursor with one or more appropriate chemicalreagents to provide a lactone product of formula Ia, Ib, or Ic (Scheme1).

As shown by Scheme 1, an acetylene can react with an aldehyde in thepresence of a phosphine, [CH₃(CH₂)₃]₃P, to form compound A, whichundergoes a ring-rearrangement reaction to form compound B in enolicform. Enolic compound B is in equilibrium with its ketone form, compoundC. Reaction of either B or C in the presence of a base such as butyllithium, sodium carbonate, sodium hydroxide, or sodium methoxide orethoxide to form compound E (Formula Ic) or F (Formula Ib). In thealternative, the enolic compound B can be subjected to reductionreaction with NaBH₄ to form saturated compound D. Compound D undergoescondensation reaction with HCO₂Et to form an exocyclic enolate, compoundG, which is then reduced by formyl aldehyde to form compound H. CompoundH can be readily derivatized to form compound I (Formula Ia) using, forexample, an alkyl halide in the presence of a base such as sodiumcarbonate, sodium hydroxide, or sodium methoxide or ethoxide.

More functionalized lactones can be prepared by readily availablesynthetic method in the art (see, for example, March, “Advanced OrganicChemistry,” 4^(th) Edition, 1992, Wiley-Interscience Publication, NewYork).

The pharmaceutically acceptable salts of the lactone compounds of theFormulae Ia-c, if in the form of an acid or a base such as an amine, canbe prepared in a conventional manner by treating a solution orsuspension of the compound of Formulae Ia-c with about one chemicalequivalent of a pharmaceutically acceptable base or acid. Conventionalconcentration and recrystallization techniques are employed in isolatingthe salt.

III. Methods of Treatment

A. Disorders to be Treated

The lactones are useful to treat pain, particularly pain associated withdisorders including cancers. Representative types of cancers includemelanoma, leukemia, breast cancer, lung cancer, ovarian cancer, coloncancer, esophagus cancer, liver cancer, and lymphatic cancer.

The lactones can be formulated into analgesic compositions. Analgesiccompositions are comprised of a therapeutically effective amount of acompound of formulae Ia, Ib, or Ic or a salt thereof and an inertpharmaceutical carrier to alleviate pain.

B. Dosages

The effective amount will be determined based on the pain to be treated,the mode of administration and the formulation. Effective dosages can beroutinely determined based on the effective dosages determined using invivo assays such as those described in the examples.

The preferred compound is alpha-methylene-gamma-butyrolactone, alsoreferred to as 4,5-dihydro-3-methylene-2[3H]furanone, “Securolide” or“LMSV-6”, for the treatment of pain. Typical doses for cancer patientsfor relief of pain are 60 mg/day given once or twice dailyintramuscularly. The LD₅₀ in rabbits for the compounds disclosed is 225mg/kg. Typical maximum dosages for humans is 60% of the LD₅₀. Toxicityin humans occurs between about 300 and 400 mg/day.

The compounds can be administered to humans for the treatment of painassociated with disorders such as cancer by either the oral orparenteral routes and may be administered orally at dosage levels ofabout 0.1 to about 100 mg/kg, advantageously about 0.5 to 60 mg/kg/daygiven once or twice a day. For intramuscularly or intravenousadministration, dose levels are about 0.1 to about 100 mg/kg/day,preferably about 0.5 to about 60 mg/kg/day. While intramuscularadministration may be a single dose or up to 4 divided doses,intravenous administration can include a continuous drip.

C. Mode of Administration

The lactone composition can be administered by any standard route,either systemically, topically or locally. Preferred routes ofadministration are by injection, orally using an enteric coating, ortopically in ointment form. The mode of administration will vary withthe type of pain to be alleviated.

The compounds may be administered alone, but will generally beadministered in admixture with a pharmaceutical carrier selected withregard to the intended route of administration and standardpharmaceutical practice. For example, they can be administered orally orin the form of tablets containing such excipients as starch or lactose,or in capsules either alone or in admixture with excipients, or in theform of elixirs or suspensions containing flavoring or coloring agents.In the case of humans, the compounds may be administered as syrup orenteric coated tablets. In addition, they can be injected parenterally,for example, intramuscularly, intravenously or subcutaneously. Forparenteral administration, they are best used in the form of a sterileaqueous solution which can contain other solutes, for example,sufficient salt or glucose to make the solution isotonic.

A preferred method of intramuscular administration of thealpha-methylene-gamma-butyrolactone is via an oil-based carrier, such asCremophor (the same carrier typically used to administer taxol). A morepreferred method is via an injectable aqueous solution. For topicaladministration, the compounds can be administered as a cream with a doseof 60 mg/12 g of an emulsion such as Vaseline®. Variations in dosage andformulation will result based on the weight and condition of the subjectbeing treated and the particular route of administration chosen as willbe known to those skilled in the art.

The present invention will be further understood by reference tofollowing non-limiting examples.

Example 1 Study of Adverse Reactions to LMSV-6 in Healthy Volunteers

Methods

Nineteen healthy volunteers participated in the study. The age of theparticipants was between 21 and 40 years with an average of 30.5±7.2years. The weight was between 150 and 190 pounds with a median of163.2±14.3 pounds and the height was 1.8 to 2.1 meters with an averageof 1.9±0.1 meters. The subjects were selected at random in agreementwith the national and international criteria and norms established forinvestigations with human beings.

The state of health of the participants was established using severalclinical evaluations, laboratory tests, electrocardiographs and thoracicradiographs. The functionality of the liver and the renal systems wasverified by chemical-enzymatic studies. Likewise, for each participant,tests of blood chemistry, pathology and urinalysis were carried out. Forthe female participants, the absence of pregnancy and/or lactation wasverified by means of laboratory tests and gynecological evaluation.

Participants were divided into three groups selected at random (n=6):

Group I (placebo) received 2.0 ml of saline solution (ClNa⁺, 0.9%),

Group II, received 60 mg of LMSV-6 intramuscularly, and Group III (n=7)received 100 mg of LMSV-6 intramuscularly. The participants underwentseveral tests used to establish the basal values of the objectiveparameters of the analysis, which included:

Lab Studies: hemogram, blood chemistry, urinalysis and coproanalysis

Cardiovascular Function: arterial tension (TA), cardiac rhythm (RC),cardiac frequency (FC) and radial pulse (PR)

Pulmonary Functions: pulmonary respiration (VP) and respiratoryfrequency (FR)

Renal Function: urinary volume and urinary frequency (FU)

Sensory System: hearing, vision, smell, taste and sensory reflexes

Skin and/or Teguments: sensitivity, skin texture, temperature andmusculo-skeletal tone

Neurovegetative Functions: salivary gland and sweat gland activities,gastrointestinal mortality and visceral reflexes

Hypersensitivity Reactions: local sensitivity and systemic sensitivity.

The evaluations were taken at the following time intervals: Time 0.0,5.0, 15.0, 20.0, 30.0 and 45.0 min.; 1.0 h., 1.5, 2.0, 3.0, 4.0, 6.0,8.0, 12.0, 24.0, 36.0 and 48.0 hours.

Results

The reports of the laboratory tests and special exams performed toverify the state of health of the participants showed the values weremaintained within the basal levels and there was no observation of anydifference with respect to the group that received the placebo.

The results of the laboratory tests performed dealing with the urinaryfunctions and the microbiological pattern found the values to be withinthe reference values for the utilized methods. Likewise, the results ofthe copra analysis also showed no pathological change.

The individual values and averages f standard deviation per group ofparticipants before and during the trials were measured to determine theadverse reaction and margin of tolerance to LMSV-6 with respect tocardiovascular parameters including arterial tension (TA), cardiacfrequency (FC), radial pulse (PR) and cardiac rhythm (RC). For healthyvolunteers, which received 60 and 100 mg of LMSV-6 and 2 ml of 0.9%sodium chloride as a placebo, the results show that in relation to thebasal values and those of the placebo control group, the levels of TA,FC, PR and RC did not change with the treatment. Likewise, there was novariation in the electrocardiograph pattern between the basal conditionsand after the study.

The individual values and the averages±standard deviations per groupinvolved in the evaluation of the effects of LMSV with respect to therespiratory functions in healthy volunteers were also measured. Theresults demonstrate that in relation to the basal values and those ofthe placebo control group, the treatment in the tested dosages did notalter the respiratory mechanics and dynamics of the participants. Therespiratory frequency (FR) was maintained in a range of 18 to 20respirations per minute during the entire test.

According to that which was observed in the basal conditions and in theplacebo group, none of the parameters evaluated dealing with therespiratory dynamic, inspiration, aspiration, tracheal respiration,bronchial respiration and thoracic-pulmonary distension and the superiorand inferior airflow, suffered any alteration.

The evaluation of the effects of LMSV-6 with respect to the renalfunction parameters showed that the values of urinary frequency inindividuals of the control group and those who were treated weremaintained within a range, without much significant variation, of3.1±0.7 to 3.3±1.5 times in a period of 12 hours of direct observation.Likewise, the average urinary volume in the same period was between434.2±213.2, 489.2±94.3 and 394.3±103.9 ml in the placebo groups and thegroups which received 60 and 100 mg of LMSV-6, respectively. Thisdemonstrates that the treatment did not affect the fundamental renalfunctions.

The data of the effect of LMSV-6 on the mental state and sensoryacuteness: auditory, visual, olfactory and taste discrimination indicatethat the treatment did not provoke any alteration in any of thefunctions or analyzed parameters. Likewise, there was not any alterationin the superficial and osteotendinous reflexes.

The data of the evaluation of the effects of LMSV-6 on cutaneoussensitivity and temperature indicate that the treatment did not provokeany change in the cutaneous sensitivity, or in the temperature of theparticipants. Likewise, there is no evidence of any alteration in themusculo-skeletal tone of any of the participants of the control groupsor the treated groups.

The treatment did not produce any alteration in the texture or moistureof the skin in any of the participants in the study, and there was nochange observed in the characteristics of the oral and nasal mucosa dueto a treatment effect.

The data dealing with the evaluation of allergic effects (reactivity),both local and systemic, indicate that there was not any manifestationof allergic reactions in any of the participants.

The data of the evaluation and effects of LMSV-6 at a neurovegetativelevel (glandular and visceral) show that in the ranges of studieddosages (60 and 100 mg), there is no evidence of any manifestation ofneurovegetative alteration at the gastrointestinal visceral level,genito-urinary level, larynx-opthalmic glands, nor cardiotonic effect;which is to say, there is no alteration at the level of the exocrine andendocrine glands.

The results of the present study affirm that LMSV-6 possesses an amplemargin of tolerance and that the maximum dosage tested (100 mg) was welltolerated by all participants. Likewise, there is no evidence, sign orsymptom of adverse reactions in any participants involved in the study.

Example 2 Administration to Cancer Patients

Securolide was administered to a number of cancer patients for thetreatment of cancer. The dosage was 60 mg/once or twice daily. Thedosage was given in an oil base or in Cremophor by intramuscularinjection.

An unanticipated outcome of the study was that patients who were onmorphine for control of pain were able to be removed from the morphineand were free from pain associated with the cancer.

The invention claimed is:
 1. A dosage formulation comprising a compoundor a pharmaceutically acceptable salt thereof wherein the compound hasone of the following structures:

wherein R₁-R₆ taken independently are a hydrogen atom or a group orgrouping selected from the group consisting of alkyl, substituted alkyl,ally, substituted allyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, heteroaryl, substituted heteroaryl, halo, hydroxyl,alkoxy, substituted alkoxy, alkoxy, phenoxy, substituted phenoxy, aroxy,substituted aroxy, alkylthio, substituted alkylthio, phenylthio,substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano,substituted isocyano, carbonyl, substituted carbonyl, carboxyl,substituted carboxyl, amino, substituted amino, amido, substitutedamido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl,substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl,substituted polyaryl, C1-C20 cyclic, substituted C1-C20 cyclic,heterocyclic, substituted heterocyclic, aminoacid, peptide, andpolypeptide groups; Z is a heteroatom selected from the group consistingof oxygen, sulfur, and nitrogen groupings in linear, branched, or cyclicstructural formats; and X is a heteroatom selected from the groupconsisting of oxygen, sulfur, and nitrogen groupings in linear,branched, or cyclic structural formats, and a pharmaceuticallyacceptable carrier, wherein the compound is in an effective amount toalleviate pain.
 2. The formulation of claim 1 in a dosage equivalent tobetween 60 and 120 mg/day given intramuscularly.
 3. The formulation ofclaim 1 further comprising a pharmaceutically acceptable carrier forparenteral, enteral, or topical administration.
 4. The formulation ofclaim 1 wherein the carrier for enteral administration is selected fromthe group consisting of a mouthwash, lozenge, tablet, capsule, solution,suspension, and granule.
 5. The formulation of claim 3 wherein thecarrier for topical administration is selected from the group consistingof a suppository, ointment, cream, gel, paste, colloidion,glycerogelatin, liniment, lotion, plaster, powder, tape, patch, aerosol,solution, and tincture.
 6. A method of treating pain comprisingadministering to an animal a composition comprising an effective amountof a compound or a pharmaceutically acceptable salt thereof in apharmaceutically acceptable carrier, to alleviate pain, wherein thecompound has one of the following the following structures:

wherein R₁-R₅ taken independently are a hydrogen atom or a group orgrouping selected from the group consisting of alkyl, substituted alkyl,ally, substituted allyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, heteroaryl, substituted heteroaryl, halo, hydroxyl,alkoxy, substituted alkoxy, alloxy, phenoxy, substituted phenoxy, aroxy,substituted aroxy, alkylthio, substituted alkylthio, phenylthio,substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano,substituted isocyano, carbonyl, substituted carbonyl, carboxyl,substituted carboxyl, amino, substituted amino, amido, substitutedamido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl,substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl,substituted polyaryl, C1-C20 cyclic, substituted C1-C20 cyclic,heterocyclic, substituted heterocyclic, aminoacid, peptide, andpolypeptide groups; Z is a heteroatom selected from the group consistingof oxygen, sulfur, and nitrogen groupings in linear, branched, or cyclicstructural formats; and X is a heteroatom selected from the groupconsisting of oxygen, sulfur, and nitrogen groupings in linear,branched, or cyclic structural formats.
 7. The method of claim 6 whereinthe pain is associated with a proliferation disorder.
 8. The method ofclaim 7 wherein the proliferation disorder is a cancer selected from thegroup consisting of melanoma, leukemia, breast cancer, lung cancer,ovarian cancer, colon cancer, esophagus cancer, liver cancer, andlymphatic cancer.
 9. The method of claim 6 wherein the dosage of thecompound is equivalent to 60 to 120 mg/day given intramuscularly. 10.The method of claim 6 wherein the dosage is up to 400 mg/day.
 11. Themethod of claim 6 wherein the compound is administered in an ointment orcream applied to the skin or mucosal surface.
 12. The method of claim 6wherein the compound is administered by injection.
 13. The method ofclaim 12 wherein the compound is in an oil or cremophor based carrier.14. The method of claim 6 wherein the compound is enteric coated fororal administration.
 15. The method of claim 6 wherein the compound isin a syrup.
 16. The dosage formulation of claim 1 wherein the pain isassociated with a proliferation disorder.